SI9111731A - Novel 3-cycloalkyl-propanamides, their tautomeric forms, their salts, processes for their preparation, use as medicaments and preparations containing them - Google Patents

Abstract

A compound selected from the group consisting of all tautomeric forms of a cycloalkyl-propanamide of the formula <IMAGE> I wherein R1 is cycloalkyl of 3 to 6 carbon atoms, R2 is hydrogen or alkyl of 1 to 3 carbon atoms, R3, R4, R5, R6 and R7 are individually selected from the group consisting of hydrogen, halogen, -NO2, azido, -CN, alkyl, alkoxy and alkylthio of 1 to 6 carbon atoms, -(CH2)m-CF3, -O-(CH2)m-CF3, -S-(CH2)m-CF3, m is an integer from 0 to 3, -CF2-Hal, -OCF2-Hal, <IMAGE> <IMAGE> n is an integer from 1 to 3, Hal, Hal1, and Hal2 and Hal3 are individually halogen, and -COR', R' is -OH or alkyl or alkoxy of 1 to 3 carbon atoms or R4 and R5 together are -O-CH2-O- and their non-toxic, pharmaceutically acceptable basic salts having anti-inflammatory activity.

Description

NEW 3-CYCLGALKYL-PROPANAMIDES, THEIR TAVTOMERIC FORMS, THEIR SALTS, THE PROCEDURES FOR PREPARATION, THE USE OF THE MEDICINAL PRODUCTS, AND THE PREPARATIONS THEREOF0

The present invention relates to novel 3-cycloalkylpropanamides, their tautomeric forms and their salts, as well as to a process for the preparation, use of these new products as medicaments and the preparations containing them.

The object of the invention are novel 3-cycloalkyl-propanamides corresponding to the general formula I:

in which:

R4 represents a cycloalkyl group comprising 3-6 carbon atoms,

R2 represents a hydrogen atom, an alkyl radical comprising 1-3 carbon atoms,

R3, R4, R5, Rg and Ry, identical or different, represent a hydrogen atom, a halogen atom, an alkyl radical, normal or branched, comprising 1-6 carbon atoms, an alkoxy radical normal or branched, comprising 1-6 carbon atoms, alkyl-2-thio radical comprising 1-6 carbon atoms, radical 0 'and ^CH 2 \ ^CF 3 »-S- (CH ₂ ) _m -CF ₃ , ^k J ^er Represents m number between 0 and 3, radical -CF2 ~ Hal, -0CF2 ^_ Hal,

F - Hal and ali

X ¹ H a 1 2

O (CF2) _n -CF-Hal3-CF3, where n represents a number between 1 and 3, Hal and Ha ^ are identical or different and Hal and Hal ₃ represent a halogen atom, or

R ₃ , ^r 4 » ^r 5» ^r 6 ^{3n r} 7 'identical or different represent a nitro, azido, nitrile or -CO-R' group in which R 'represents a hydroxy, alkyl or alkoxy radical comprising 1 -3 carbon atoms, or R4 and Rg together form the group -O-CH2-O-, their tautomeric forms as well as their addition salts with mineral or organic bases.

In the general formula I and in the following:

by the group cycloalkyl comprising 3-6 carbon atoms is understood to mean the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, the alkyl radical comprising 1-3 carbon atoms means the methyl, ethyl, propyl, isopropyl radical, the alkyl radical comprising 1-6 carbon atoms, in particular the radical methyl, ethyl, propyl, isopropyl, butyl normal or branched, pentyl normal or branched, hexyl normal or branched, under the alkoxy radical comprising 1-6 carbon atoms, is understood to mean, for example, methoxy radical , ethoxy, propoxy, isopro-3 poxy, butoxy normal or branched, pentyloxy linear or branched, hexyloxy normal or branched, under an alkylthio radical comprising 1-6 carbon atoms, for example, the term methylthio, ethylthio, propylthio, isopropylthio, butyl normal or branched, pentylthio normal or branched, hexylthio normal or branched, a halogen atom is understood to mean specifically a fluorine, chlorine or iodine atom.

Addition salts with mineral or organic bases may for example be salts prepared with mineral bases such as salts of sodium, potassium, lithium, calcium, magnesium or ammonium. Organic bases include methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procain, lysine, arginine, histidine glucamine.

Among the products of the invention, in particular, derivatives corresponding to formula (I) above may be mentioned, as well as their salts, characterized in that, in said formulas I, R ₃ , R 6, R 5, R 5 and R 5 are identical or different, represent a hydrogen atom, a fluorine atom, chlorine, bromine or iodine, methyl, ethyl, terbutyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, pentafluoroethoxy, bromodifluoromethoxy, acetyl, hydroxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl together, the group O-CH 2 -O-, R 2 represents a hydrogen atom or a methyl radical, R 2 has a pre-existing meaning as well as their addition salts with mineral or organic bases.

Among the latter, in particular, derivatives according to formula I above can be mentioned, characterized in that R4 represents cyclopropyl, R2 represents a hydrogen atom or a methyl radical,

R _3, R 4, R 5 'R and Ry are identical or different, represent a hydrogen atom, a fluorine, chlorine or iodine, the radical methyl, trifluoromethyl or nitro, as well as their addition salts with inorganic or organic bases.

Among these latter are particularly the derivatives of the formula I whose names follow;

- 1- (4-nitrophenylcarbamoyl-2-cyclopropyl-2-oxopropionitrile,

- 1- (4-chloro-3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxoprop and o n i t r i 1,

- 1- (3-methyl 4-trifluoromethylphenylcarbamoyl) -2-cyclic footwear2-2oxopropionitrile,

- 1- (4-cyano 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and those tri1, as well as their addition salts with mineral or organic bases.

The invention also provides a process for the preparation of novel 3cycloalkyl-1-propanamides, as defined by formula I above, as well as their salts, characterized in that the product of formula II reacts:

in which R ₃ , ^R 3> ^R 4 » ^R 5» ^R 6 ^R 7 ^{2e have the indicated} meaning, with an acid of formula III or a functional derivative of this acid:

(III)

CN

Hi to obtain a product of formula IV

R

R, '5

(IV) in which R _? , R3, R ^, Rg, Rg and R? the meaning already indicated which then reacts with sodium hydride, if necessary, in the presence of a catalyst such as, for example, imidazole and then with the product of formula V:

Hal-CO-R _X (V) in which Hal represents a halogen atom, and R _x has the 2e demonstrated importance of obtaining the corresponding product of formula I, which is isolated and, if desired, converted to a salt.

In a preferred embodiment of the invention, the preparation process described above is characterized in that:

the reaction of a product of formula II with an acid of formula III or a functional derivative thereof is carried out in the presence of diisopropylcarbodiimide or dicyclohexylcarbodiimide in an anhydrous organic solvent, such as tetrahydrofuran or dichloromethane; to phosphorus pentachloride.

-break of the product of formula IV with sodium hydride is carried out in an anhydrous organic solvent such as tetrahydrofuran.

The products of formula I are acidic. The addition salts of the products of formula I can be advantageously prepared by reacting the mineral or organic base with said products of formula (I) in stoichiometrically acceptable proportions. Salts can be obtained without isolating the appropriate acids.

The products of the present invention have very interesting pharmacological properties. Particularly remarkable anti-inflammatory activity is observed. They inhibit, on the one hand, the inflammatory phenomenon triggered by irritants and, on the other hand, the reaction of retarded hypersensitivity by preventing the activity of immune cells on a specific antigen.

These properties are further illustrated in the experimental work.

These properties justify the use of novel 3-cycloalkylpropanamides of formula I, as well as their addition salts with pharmaceutically acceptable bases, as medicaments.

The present invention also has the object of using novel 3-cycloalkylpropanamides, as defined by the general formula I, as well as their addition salts with pharmaceutically acceptable mineral and organic bases, as medicaments.

Among the medicaments, the object of the invention is principally contained in the medicaments, characterized in that they consist of novel 3cyclial or 1-propanamides corresponding to the formula I in which R3, R4, Rg, Rg and R ?, identical or different, represent hydrogen atom, fluorine, chlorine, bromine or iodine atom, methyl, ethyl, tributyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethyl, pentafluoroethoxy, bromodifluoromethoxy, acetyl, hydroxycarbonyl, methoxycarbonyl, nitro, and nitrocarbonyl, methoxycarbonyl, nitro together they form a -O-CH2-O- group, R2 represents a hydrogen atom or a methyl radical, R1 has an already indicated meaning as well as their addition salts with pharmaceutically acceptable mineral or organic bases.

Among the medicaments, the object of the invention is more specifically restrained by those corresponding to formula I above, wherein R1 represents a cyclopropyl group, R2 represents a hydrogen atom or a methyl radical, R3, R4, Rg, Rg and Ry, identical or different, represented by an atom hydrogen, fluorine, chlorine or iodine atom, methyl, trifluoromethyl or nitro radical, as well as in their addition salts with pharmaceutically acceptable mineral or organic bases.

Among the preferred medicaments of the invention, the following are specifically mentioned:

- 1- (4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

- 1- (4-cyanophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

- 1- (4-chloro 3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile,

- 1- (3-methyl 4-trifluoromethylphenylcarbamoyl) -2-cyclic footwear2-2oxopropionitrile,

- 1- (4-cyano 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile, as well as on their addition salts with pharmaceutically acceptable mineral and organic bases.

For example, these medicines are used in treatment

-8 ~ rheumatoid arthritis and chronic inflammatory diseases of immune origin or not (transplantation, organ transplantation, etc.).

The usable dose varies depending on the product used, the subject of treatment and the agent and can be from 0.1 to 200 mg daily by the oral route.

The invention also has pharmaceutical compositions containing as at least one said derivative or one of its addition salts with pharmaceutically acceptable bases as the active ingredient.

As medicaments, derivatives of formula I and their addition salts with pharmaceutically acceptable bases may be incorporated into pharmaceutical compositions intended for the digestive or parenteral route of administration.

Pharmaceutical preparations may be, for example, solid or liquid and administered in pharmaceutical forms currently used in human medicine, for example, as simple tablets or dragees, gelatin, capsules, granules, suppositories, injectable preparations, which are obtained by conventional techniques. The active element or elements may be incorporated in excipients commonly used in these pharmaceutical preparations, for example talc, arabic gum, lactose, amidone, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fats of vegetable or animal origin, paraffin derivatives, glycols, various moisturizing, dispersing or emulsifying agents and preservatives.

The invention has the same meaning for an object as industrial new products and, in particular, for industrial products required as intermediates for the preparation of products of formula I, products of formula IV:

(IV)

in which R3, R ^, Rg, Rg and R? the meanings indicated above, and in particular those wherein R3, Rg and R7 represent a hydrogen atom, R4 represents a methyl radical and R2 and Rg have the above meanings with the exception of a chlorine atom or a methyl radical1a.

They can be obtained by an operating mode analogous to that described by A. Nohara, T. Ishiguro et al, in J. Med.

Chem (1985) 28 (5), 559 - 566 next schemes and: , Os. s nh .0 / NHCOCH.CN i I I ² * L 1 A ² t R- l CHO L 1 0 0

The products of the formula II used at the beginning of the process are commonly known products and can be obtained by diazotization and then reduction of the corresponding n i troanes 1 by a process known to those skilled in the art.

The nitroanilines used can be obtained as indicated, for example, in TP. Sura et al., Synthetic Communications (1988) 18 (16-17), 2161-5.

Certain anilines of formula II can be obtained according to European patent EP 206951 or by reduction of the corresponding nitrobenzenes, which are commonly known.

Some nitrobenzerias are new and may be obtained as indicated later in the examples.

We will now give non-limiting examples of implementation of the invention.

EXAMPLE 1: 1- (4-Trifluoromethylphenylcarbamoyl) -2-cyclopropyl 2-oxopropyl yttrium

Level A: 4-Trifluoromethyl cyanoacetanes

8.6 g of cyanoacetic acid and 13.5 cm @ 4 - (trifluoromethyl) aniline are dissolved in 100 cm @ 2 of tetrahydrofuran, 16.4 cm @ 2 of diisopropylcarbodiim is added after 10 minutes of stirring without cooling. During the addition, the temperature varies from 20 to 60 ° C; the mixture was stirred for 16 hours at ambient temperature, filtered and the solvent was evaporated, the residue was brought to ambient temperature, filtered, washed with ethanol, methylene chloride or hexane. Drying under reduced pressure at 60 ° C for 3 hours gives 18.85 g of the desired product, mp: 195-196 ° C.

Step 8: 1- (4-Trifluoromethylphenylcarbamoyl) -2-cyclopropyl 2-oxopropionitrile

To 3 g of the product obtained in stage A suspended in

Oh

100 cm &lt; -1 &gt; of tetrahydrofuran, 0.88 g of sodium hydride is added and stirred for 30 minutes at ambient temperature. 1.30 cm @ 3 of cyclopropanecarbonyl chloride was added over 10 minutes and the mixture was stirred for 16 hours at ambient temperature. Add 1 cm3 of water for 10 minutes only, acidify with 2 M hydrochloric acid and extract with ethyl acetate. The organic phase is dried, the solvent is evaporated. Remainder

O was heated to 15 cm &lt; 3 &gt; ^{J of} methylene chloride, diluted in ether to give 2.72 g of the desired product, mp: 212-213 ° C.

By performing in accordance with the above operating method, starting from the corresponding compounds, we obtained the products of the following examples:

EXAMPLE 2: 1- (3-chlorophenyl and 1 carbamate and 1) 2-cyclopropyl 2-oxoprop and he and t r i1.

EXAMPLE 3: 1- (4-Trifluoromethylphenylcarbamoyl) 2-cyclopropylbenzene and he and t r i1.

EXAMPLE 4: 1- (4-Trifluoromethylphenylcarbamoyl) 2-cyclopentyl2-oxopropionitrile.

EXAMPLE 5: 1- (4-Trifluorophenylcarbamoyl) 2-cyclopropyl-2-oxo-propionyl and tris.

EXAMPLE 6 1- (4-Chlorophenylcarbamoyl) 2-cyclopropyl 2-oxopropyl o n i t r i 1.

EXAMPLE 7: 1- (4-Bromophenylcarbamoyl 2-cyclopropyl 2-oxopropyl) 1.

EXAMPLE 8: 1- (4-Iodophenylcarbamoyl) 2-cyclopropyl 2-oxopropyl and tertiary,

EXAMPLE 9: 1- (4-Trifluoromethoxyphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 10 1- (4-Nitrophenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 11: 1- (3,4-Dichlorophenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

Level A: 4′-iodo cyanoacetanilide

To a suspension containing 35,25 g of phosphorus pentachloride in

Oh

250 cr of methylene chloride, 14.41 g of cyanoacetic acid are added over 2 minutes while stirring and maintaining the ambient temperature. Reflux is heated for 30 minutes, stirring is carried out under flow.

- 12 nitrogen over 2 minutes, add 24.75 g of 4-iodoaniline and

O reflux for 2 hours, cool, pour into 300 cm-3 of water. The mixture is stirred for 1 hour, filtered, the residue is taken up in aqueous sodium bicarbonate solution, filtered, the solid residue is washed in water, ethanol and then dried at 60 ° C under reduced pressure. 29.51 g of the expected product is obtained, mp. : 216-218 ° C.

Step B: 1- (4-iodophenylcarbamoyl) 2-cyclopropyl 1-oxopropion yttri1

When carried out as indicated in step B of Example 1, using the 4′-iodo c i anoacetari i 1 i yes, the compounds prepared in the previous step A yields the expected product.

Example 12: 1- (4 ~ Bromo 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile

Step A: 4-Bromo 3-methyl c and aryoacetane and 1 and d

0.457 g of cyanoacetic acid and 1 g of 4-bromo 3-methyl-aniline are dissolved in 30 cm of methylene chloride, 1.135 g of dicyclohexylcarbodiimide in 5 A of methylene chloride are added with stirring at 40 ° C for 2 minutes. During addition, the temperature remains above 40 ° C; the mixture was stirred for 1 hour at ambient temperature, filtered dicyclohexylurea, evaporated solvent, the residue was chromatographed by elution with methylene chloride containing increasing amounts of ethyl acetate. We get the expected product in 87% yield.

Step B: l ~ (4 ~ bromo 3-methylphenylcarbamoyl) 2-cyclopropyl oxoprop and he and t r i1

To 300 mg of the above product dissolved in 12 mg

About cm- 'tetrahydrofuran, add a catalytic amount of imidazole while maintaining stirring under a nitrogen atmosphere. 626 mg of sodium hydride was added, stirred for 15 minutes at ambient temperature. 124 mg of cyclopropane carbonyl chloride is added over 3 minutes and stirred for 2 hours at ambient temperature. The reaction medium is poured onto ice water, acidified to pH = 2 with IM HCl, stirred for 1 minute, the precipitate formed is filtered, washed in water and then in ether to give the expected product in 88.3% yield.

EXAMPLE 13: 1- (3,4-Methylenedioxyphenylcarbamoyl) 2-cyclic propyl 1 2 - o k s o p r o p i o n i t r i 1

Level A: 3,4-methylenedioxy cyanoacetaniyl

To a suspension containing 685 mg of phosphorus pentachloride in

About one cm of methylene chloride is added over one minute 279 g of cyanoacetic acid while stirring and maintaining the ambient temperature. It is refluxed for 30 minutes, stirred under a stream of nitrogen for 2 minutes, 300 mg of 3,4-methylenedioxyaniline is added and heated for 10 minutes with reflux, cooled to the temperature of the ocular face and sucked into 10 cnr of water. The mixture was stirred for 30 minutes, filtered, washed with water and then with ether and ethyl acetate. 330 mg of the expected product are obtained.

Step 8: 1, (3,4-methylenedioxyphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile

By performing as indicated in step B of Example 1, using the 3,4-methyl-endioxy-cyanoacetanes 1 id obtained in the previous step A, the expected product is obtained.

By performing the above operation method based on the corresponding compounds, we obtained the products of the following examples:

EXAMPLE 14: 2-Cyano 3-cyclopropyl 3-oxo N-methyl N- (4-chlorophenyl) propionamide.

14-EXAMPLE 15: 1- (4-Chloro 2-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 16: 1- (3,4-Difluorophenylcarbamoyl) 2-cyclopropyl 2-oxopropyl triethyl.

EXAMPLE 17: 1- (4-Methoxyphenylcarbamoyl) 2-cyclopropyl 2-oxo propionitrile.

EXAMPLE 18: 1- (4-Cyanophenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 19: 1- (3,5-Dichlorophenylcarbamoyl) 2-cyclopropyl 2-oxo-propionic and trio.

EXAMPLE 20 1- (4-Chloro 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 21 1- (3-Trifluoromethylphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and he and tr.

EXAMPLE 22: 1- (4-Methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionyl tri 1.

EXAMPLE 23: 1- (4-Chloro 3-trifluoromethylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 24 1- (phenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 25 1- (3-Methyl 4-trifluoromethylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 26 1- (4-iodo 3-methylphenylcarbamoyl) 2-cyclopropyl 2 oxopropionitrile.

EXAMPLE 27: 1- (4-Fluoro 3-methylphenylcarbamoyl) 2-cyclopropyl

2-oxoprop i he i t r i1.

EXAMPLE 28 1- (4-Cyano 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 29: 1- (4- (2,2,2-1rifluoroethoxy) phenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 30 1- (3-Methyl 4-nitrophenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 31: 1- (4-t-Butyl phenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 32 1- (3-Methylphenylcarbainoyl) 2-cyclopropyl 2-oxoprop and he and tr 1.

EXAMPLE 33 1- (4-Trifluoromethylthiophenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

EXAMPLE 34 1- (4-Methoxycarbonylphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and he and t R 1.

EXAMPLE 35: 1- (4-Acetylphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and he and tr.

EXAMPLE 36: 1- (3,4-Dimethoxyphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and he and t.

EXAMPLE 37: 1- (3-Chloro 4-methylphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and one and a third.

EXAMPLE 38: 1- (4-Methylthiophenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile.

-16 EXAMPLE 39: 1- (3-ethyl 4-nitrophenylcarbamoyl) 2-cyclopropyl

2-oxoprop and they run.

EXAMPLE 40: 2-Cyano 3-cyclopropyl 3-oxo N-methyl N- (3-methyl

4-Trifluoromethylphenyl) propionamide.

EXAMPLE 41: 1- (4-Bromodifluoromethoxy 3-methylphenylcarbamoyl)

2- Cyclopropyl 2-oxopropionitrile.

EXAMPLE 42: 2-Cyano 3-cyclopropyl 3-oxo N-methyl N- (4-cyanoferry 1 propionamide.

EXAMPLE 43: 2-Cyano 3-cyclopropyl 3-oxo N-methyl N- (4-nitrophenyl) - p r o p i o n a m i d.

EXAMPLE 44 1- (3-Methyl 4-trifluoromethoxyphenylcarbamoyl) 2cyclopropyl 2-oxopropionitrile.

EXAMPLE 45: 1- (3 ~ Methyl 4-pentafluoroethylphenylcarbamoyl) 2cyclopropyl 2-oxopropionitrile.

EXAMPLE 46: 2-Cyano 3-cyclopropyl 2-oxo N-methyl N- (4-bromo

3- methyl1 phenyl) propionamide.

EXAMPLE 47: 1- (4-Chloro 3-ethylphenylcarbamoyl) 2-cyclopropyl 2-oxoprop and he and t r i1.

EXAMPLE 48: 1- (4-Carboxyphenylcarbamoyl) 2-cyclopropyl 2-oxo propionitrile.

EXAMPLE 49: 1- (4-Cyano 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionyl ii.

-17Preparation of 1- (bromodifluoromethoxy) 2-methyl 4-aminobenzene used at the beginning of Example 41.

0.92 g of sodium was dissolved in 30 cm ^{3 of} ethanol and 6 g of 2methyl 4-nitrophenol was added. The solvent was evaporated under reduced pressure, then benzene was added. This sodium salt is introduced into a mixture containing 24 cm ³ dimethylformamide, 30 cm ³ dibromodifluoromethane and a little ethantiol as a catalyst. It was heated at 70 ° C for 10 hours and poured onto ice and extracted with ethyl acetate. Wash with aqueous 0.5 M sodium hydroxide solution, then with water, dry and evaporate the solvent under reduced pressure. Chromatography on silica (eluent: ethyl acetate-hexane 4-96) yields 0.20 g of 1- (difluoromethoxy) 2methyl 4-nitrobenzene and 3.35 g of 1- (bromodifluoromethoxy) 2methyl 4-aminobenzene, which is hydrogenated in the presence of palladium on activated carbon and we get the expected product.

Preparation of 4-amino 1-trifluoromethoxybenzene used at the start of Example 44.

In a sealed bottle, heated at 175 ° C for 4 hours, 0.3 g of 1 (bromodifluoromethoxy) 2-methyl 4-nitrobenzene, 0.120 g of antimony trifluoride and 0.02 g of antimony pentachloride as catalyst. The mixture was diluted with ether, washed with water, dried and the solvent was evaporated under reduced pressure; 0.13 g of 2-methyl 4-nitro 1-trifluoromethoxybenzene is obtained, which is hydrogenated in the presence of palladium on activated carbon to give the expected product.

Preparation of 2-methyl 4-amino 1-pentafluoroethyl benzene used at the beginning of Example 45.

2.36 g of 1-iodine 2-methyl are stirred under argon in an argon bottle

Of 4-nitrobenzene and 2.2 g of powdered copper (Org. Syrithesis Coli. Vol. II (1948) 445, washed in water, acetone, dried under reduced pressure) in 10 cm ^{3 of} dimethylformamide. Cool to -60

18 ° C and 11 * 5 g of pentafluoroethyl iodide are added, stirred at 160 ° C under a pressure of 3.5 bar for 16 hours, cooled in ice and allowed to stand at room temperature. The mixture was poured onto ice and extracted with ethyl acetate. Rinse in water, dry and evaporate the solvent under reduced pressure. Chromatography on silica (eluent: pentane with 2-3% dichloromethane) yields 1.5 g of 2-methyl 4-nitro 1-pentafluoroethylbenzene, which is hydrogenated in the presence of palladium to give the expected product.

The spectrometric analyzes, microanalysis results, yields and melting points are given below in the tables.

-19O rl «J * r * rr rt n

H

O (M n

CM

About m

(—1 in

IM in

Oh

CM and rl

Μα mO «3 · rt r-l in

M m

rf

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CM and r-l and and r-l

CM

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CO., LTD

VO and h r-l M (M * r-l O

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H

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VO r-l r-l

CM

VO rl <m n ·. co tt 'O VD —in o o

O rl • d · r * in

About m · m

rH

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VO o

co and cH

TABLE

and

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rH vO rI tt

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M and rt and tin rH and o

and lO rH H H VO CO H to% in M- CO O CO

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n rl CM -vo co o rt rt M ¹ rl '• MΨ a) σν o «f rt rl rt m · rt rl rt rl rt rt s

CM 'rt O VO CO rt r-1 «. rt r * tt υ o '-Oi rt rt O rt

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TABLE I (continued)

21TABLE I (continued)

o this one tr 0 \ CN this one * » this one ca. r-ι in o and Oh m this one «• ro CO., LTD n ie · r-l tn o ro ro tr v m ao and cape - H ri ci this one ri p- n in m ri this one k r> ·. this one this one CN this one o ΙΛ Oh o in · and rt and - CM co r-l cn rt tf ro ro m tr m CN this one rt o r-l CM H ri this one ri n rl ro CN r- this one o this one * ri this one this one Φ o 03 o o o o o n · m this one tr cn f- · * rt ri n o n · ro and o m o l £> O rt and ri * h in ri CN r-l O this one this one co ·· ro CM CN CN Oh Oh this one o ro ** H % ri »Ri and o n ri 0 \ cn o Z * ta and ω ro « o - co ·. with - ri ri ro ri ro Ό O m m In m this one this one - (N H Γ- r-l * - * cn this one o o ro o z CN CN m cn CN cn n · n υ · * H this one ri σι h 10 ω cn ro - o o ri and ri this one ri ΙΠ o n - o this one CN - ri this one and - ro cn 4J ro cn lO Oh m <· “·» « CM O ro H O r-l pt - m this one Γ- Z cn O rt * ri ω cn CN and cn ri r- υ this one ro «· CL ri this one ri 00 H 00 «S ta-z tA cape O this one (rt z — s . — That 03 and m CM - ro z— » Z - Z this one (N - H this one o Oh Z-% O Z o υ cm U o Oh pt CN ri Z rt in r- < tataz «« 3 » σι - ca. this one rt CN this one U - --- in rt o CN m cn r-l o this one o t-O o O ri 03 H h * h cn ri Oh O rt co cn H o m CN o ri pi ri CN * · CM this one rt ta H this one Oh ri CM rt (N m Oh and CN n this one CM - -o this one rt - CM this one tf o -O this one T cn z— * Oh ro r ^ in Z- » K H X ri K H Z ri X o X rt X S z z in z rt Z rt z - * - this one Oh, that one ta_Z this one VmT this one * w « »· m o o tn and o ro r-i o ri ύ} o about and 03 cn O 03 ®> cn (N o o and no (N n m «r rt o CN rt rt CM rt n H n H m H CN ri n r4 rt rt rt in ro ro 0 ro 1 this one this one ω CN m θ ' h · ro cn + J cn and m en ro P « n ro 4J ri H ri ri rt ri (N ri Λί P «Λ» «V <x> Vf Λ » <N> <# • H Oh « CN and m Oh rt CN P 0 10 ro rt · » ro and r · Q H Y Y Y l> - Y Y Y Y Y Y m CN K M Ph.D. K w X X X X X A in I —Σ t JL J [f * | fl ** A J ^s Λ} A (far Λ n KA, kz j 3 kk V ¹ k J J • ul Oh o Λ a φ T E M ffl ^ ko T r-C υ T ri in A T & 4 T o o You υ cj Z υ Ζψ i U. M <1) H CN n * j · m ro pt ro Ch o e H H r-C rt ri r-l r-l ri ri CN Ul cu

- 22 TABLE I (continued)

-23o

CM

TABLE I (continued) and

Ch o

CM

M-

X X - 10 X X d and m and - 10 o d o (M about and io in M · o M> o Oh X n io <m m n «T d m and o d d Γ * r-i d d rl rl and x M * x * in - Oh x d X X X X d o o eo O f ' cm n CM d d o h «T 10 cm r- o co 10 CM m M * X M * n n - tr <r «Tf m m o Oh d d χ d If) d χ d d r-l d o M · m o r- and Oh x - m - CO - r- X X X X d d o o> o - m co and o C0 d 10 o in and CM co and X X «# In «Φ X n cm and - and and and and o o H (M H O h ca r-l 00 d d d rl CM and r- o CM X <0 d CO., LTD and o d * »D - co - Oh - CO X X ** d X C0 d d 1 and O - and cm o and o o co co ε σι - r- o r-l 01 co - 10 10 d r- «- X X in «Τ O «» Σι M> - in r- m m 10 - in rl o o rl 10 rl oj H O H CM H (N d rl Γ- d 1 * · r- σι * Oh X 01 o CO., LTD r- o and o L. * d - Oh -CM X d -X X - co χ d d d CD o O r-l O - o CM d x-X CM d CM - CM 01 and o o - (M - r * · with - O - X X -M and o and - rf m io r- in co and O o 10 O o o <U d d r-l in r-l O rl n H d d («1 rl in m M · CL H r- H o (M 3 CM d 10 CM (Λ ** H -01 X X χ d ** H X and ri χ d d d tn o about and o n o d Tf X CM - o io n * m - CM d * CM - X X m o 10 O 10 o io r- 0 o 10 (M «? 10 O O ' o H f · * · H CM H H rl 01 d Lf) d and rl CM CM r- r- Oh x o CM - CM CM CM CM * d * d - Oh - «H * · H s <Ή d CM d »- • s - · CM / »~ X X ^ x X - X - X o X - X - Z in - with - X X in o In O ϋ r-l in o 0 H 0 «-R CM In o o o «- * · - CO X --- r-t Oh Xw ** w o —Co n CM and cm o o o o M · rl O n CM and c * i CM CM CM CM M H CM r-l CM CO., LTD O n O rl Oh (M rl O rl CM d o CM CM rl 6j Oh Oh d Oh (M - CM - CM rl CM - (M - (M CM - CM - χ X o Oh X 10 CO., LTD CM Oh o o -10 - CM -in -in d -10 - n - in CM m - CM —- CM CT) H - n - C0 - n - n d n K H X H X r-l X H X rl X CO., LTD X rl X rl n rl X X X H X X X X X x X X X X * »- * X * - * X X X X O o o o about m m o «Ί rl O M · o o o r- o o d d CO 10 σι «r 0 \ d «0 C- C0 O C0 rl co r- o co Γ- n CM CM CM CM n n CM n CM CM CM «i CI M ¹ CI M n ri n H n r — i n h Π K d d (Ό rl d d d d in co and (M 10 r- c- 1 1 1 Oh 1 -P t 1 o H 10 n Oh o i n 4J CM r-l CO., LTD 10 «F d (M H d rl CM

CM

Ά

U

d) e

Ή

M

CU γγγγγγγγγγ

rl <M

CM

CM n

CM «you

CM in

CM

CM

CM «

CM

Ol

CM

About cn

-24TABLE I (continued)

TABLE I (continued)

and «. H s rt and and rt σ io σ o rt H k * «> he o rt he Ol H o % , —Χ z-s rP rt -o rt fp <p rt s Mr Rücker r- and co «. t rr s σ H S o · * * o s n σ r- and and rt Oh o co o r- o (P Ol o rf o rP rr rr rt co m Ol o- pp he co · » co m Ol H o · τΡ fp cP • X o <% rt X rp o o ,. o rt co o rt m σι > CN V σ X Ip X -r o o 'Τ V) Mr Rücker o «Oh rt 00 o CO., LTD rt fp o o co rP s — z o m «K S s co o m (p % σ rT and and o fP X fp X o fp and OJ c0 <P σ (P 01 rt rt rp r. rP Ol r ~ and H CO., LTD rr o rt and X a) m H <P v ip fp * co * » s-z s o s and k. o o k. * rt o and o and o ip zs z ”k »P s Oh o o X OJ m n «T 10 Mr Rücker and co rt cO rf rt n and cP rP co X s-Z * P K rr Oh rt co fp rt rP S o rt ip o iP iP co s o H σ k. σ in k. * * and * ·· o Γ ' σ OJ m OJ Oh « rt Oh o % and rt o 00 rt CO., LTD tP rp co H o n rt σ rt and θ ' s s and σ rt rt rr σ n 'x- ^z fp rP σ S S z ~ k z-v (P fp H (P H σ fp X o r rP 1 o r- CJ 10 and σ «K s o o- e «. σ σ σ rz 'k · «· s k » o o * · r- χ rt rt X o o ·% and CO., LTD o and - o o rt 10 o Oh rt r- fp Oh d o (P K t> · B 10 co rt ip σ co CJ * and m v θ ' Ol 10 σ fp fp rr o «R X * fp L · H σ s. o rP cape on ip k. k. s rt fp rP and z-x rp Φ pP σ -rt σ rt rt rP Mr Rücker Z *> + J v m (N o z ^ k n OJ s s χ «0 B ** jt: o σ \ 0 tP e B ' o o rt Ol o o rt o * - · o <u rp σ H s-z · o rt fp fp Ol co CN s fp o CO., LTD o. σ s M o co g 01 «K s rt o rt o rt co fP V) fp o Oh o rt · - OJ σ o o ip fp tP σ fp co ip Ol Χ- » »P CJ cn 'r rt »P rt co o Oh X H Ol rt σ % k o Ol OJ X X X - S - > —1 o H in P k. -co o rt 01 iP rt o o z-- » o <P 0_z z-s v rr » s s o rt co θ ' o M and rt (N o n) s Mr Rücker β Z-S OO and o o CO., LTD rt H rt o- S-z s—. rr Ol Γ tP z — s s — z - Mr OJ r- OJ r- 10 rt rt rP σ Oh o rP o M and OJ CO 'Z rt co OJ X Η rr K rP OJ · * ✓ Ol rr in kfc rp OJ H o X X χ Ol 01 s o s o σ on co o k. σ o o and o OJ fp o C ' and kk n m rt σ \ Ol o m o rt o rt o rt rt σι σ / • S rP s % * σ rr o σ X OJ o < Ol o * * rt οι Oh X H ZS r — k OJ OJ σ CN o Ol (P Ol »P z-s rP rP X Mr Rücker and g <P CJ rt rt w and S S S-Z s SZ s— * S— * K s s X r- S s s s '· - * sz x o o o o o σ <-t o o o rt x o o o o o o o 10 OJ co rp 10 o co o 10 σ rt o σ rt co co σ fP Ol N H OJ (p n rr O he OJ 01 fp rt Ol OJ Ol o Ol rt Ol fP H n rp m rP H he rt he rP θ ' he (P rt fp fp rp Ol o rP 1 fp -r ιθ σ ω rf rr Ol co rt in 1 1 1 1 1 1 1 1 1 0 rP Ol n co co Ol OJ Η σ co o -P rr Oh o · co m 10 OJ θ ' O rt -P rP rt fp rP pp pp fp rP fp rP rP «U \ 7 r l / 77 r v λ7 V / r v v r v v « Y Y V Y Y Y Y Y Y Y (P Ol X X X X X X X X X S X in

-26TABLE I (continued)

-27TABLE I (continued)

Λ » X r » if> 1 and * < r « rrt m Λ » σ » Ό Z - 1 te I cn CO., LTD r-l o (4 ^C » ^c Oh ω e 2 - 1 te 1 c o m «R 3 c XJ ω rtJ a o Oh <* h ♦ r- | co CN o ^N Λ3 - | te 1 * r- C cr \ σ « m and CM C s CM % m r ~ i Π3 h n rrt a e h ² H E ⁿ and rrt E vn «F (N cn 0 m r-1 l-1 in o. . " • te te · «H Χ-Χ e mirt - Ό te 1 (N with N te E E II <N E E N * «- Η and 3 · CN S— * N χ <0 X Garden, m K V CN> rt) rrt σ - - || <N te II ffi (N n> te r-l Hj K · - - i— rx · * x p rt-S T3 n (N xrrt • you 0 χ «a x: rt- * W te E X U n O, Ό E H> 1 χ- * 0 te H '-, · -' N · p E Garden · O - <rrt CN CU H N ¹ O <C -H χ 0 v- » r-l χ 1 P rrt r — l σ> te CO E t »· * ϋ sx> CN • «b te s rt-te te »Te - N N s b (X- rt * te III 1 χ V) I N ^ rt. B «Te te 1 II X S »-Rt t ^ 4 Φ wnh. K ιή cn χ >> II H <# te Garden · «M K N b -H, χ ' E cn Φ H E χ CU> h m χΌΐ ΟΌ W v- · te w CM II X Μ X σ CN oo h k ao σ 2: X X <N 0 1 «0 • you · «- rrt Ό '- «M> E cape if H Ό H υ σ U) κ · · · · te ΙΕ χ 0 O 1 E rrt CN χ · χ σ · Χ g n te-rt O r4 <· -% * »n r — l 1 * · M C π B M υ Π £ χ 1 H Q □ te OM ^ I in cn L | 0) e σ o • H cn Ν ' M Oh

-28TABLE I (continued)

o Oh rt '' and OJ m o o co rt H ri rt 0J H o ri 00 rt s co rt tf Oh o OJ r K ω tf ri o o o n v ri ri rt ri o ri rt tf rt rt OJ o and o o tf tf Oh H H o ri n m ri ri ri Oh «. ri ri rt ri OJ n Oh and rt rt tf ri · m o Oh and tf Oh H ri σ ri ri ri Oh CO., LTD OJ OJ rt ri ri Oh - ¢ 0 ri ri rt in co ri σ m co o OJ co 0- s * » CO., LTD and rt * and - o o m ri * Oh o H O σ m .-j s. CM H (M ri cn n tf o co CM n 1 - σ r-l ri rt ίο σ H K s o o and o O - rt rt CO., LTD ri h rt rt ιώ H o Oh and with ID Oh and ri n r- co h σ About the CD tf σ ri tf tf co σ o OJ tf * · H H ri - co m H ri ri -Z o r- r-l φ O) - rt rt OJ * K rt rt rt ό m o o CD r- ( O OJ o Oh 0 r- (C0 OJ ri ri ri H o «R ri and and 'H K0 ri tf m Oh H ri ri * · Ri ri ri ri ri fr-1 »***. z-rt rt 2 ' rt rt 2 H --rt rt rt rt In o o o In O a cj Oh and ^ o h · r> rt-o In the cape σ d CO OJ and tn CD OJ '-rl tf CD σ H H ri O r-t tf 1-1 ri ri H Oh o OJ - * % OJ ' OJ - rt * n o o OJ oj tn o o - m n r- rt vT “CO n- z *, cm OJ CO., LTD - OJ I-t and m K H OJ ri K H E r-t H N 2 a a 'rtZ rt. rt v 'rt <- * rt rt o o o o o m o m tf o o co o c0 n OJ CO CD > m fM tf OJ tf OJ O OJ OJ 01 OJ O) m rl n ri OJ H OJ ΓΊ ri n «-t 01 m and m o o in m m - m r- σ 0 1 1 h CM 1 t 1 1 and H H tf ω and co σ + J ID tf H tf rt n CD + J H ri ri ri ri ri ri H o $ γ V V V V V V V M n rt O1 2 hi E a E E E E U in U

H tf

Ol tf n

tf .tf tf and tf

CO tf ttf

CO tf z 'rt u. ffl

TABLE I (continued)

-30 EXAMPLE 50

We have prepared tablets that meet the following formula:

compound of Example 1 20 mg excipient q.s.p. to the 150 mg tablet (listing of excipients: lactose, amidone, talc, magnesium stearate)

EXAMPLE 51

We have prepared tablets that meet the following formula:

compound of example2 20mg excipient q.s.p. to the 150 mg tablet (listing of excipients: lactose, amidone, talc, magnesium stearate).

PHARMACOLOGICAL ACTIVITY

BIOCHEMICAL TEST PROCEDURES

The first test

Carcinoma-induced edema of Sape rats (PO-R).

One hour after oral administration of the test compound or vehicle for the control experiment, inject 1 mg carrageenan dissolved in 0.2 ml saline into groups of rats (n = 6-12, CFHB males weighing between 160 - 180 g). the cheekbone of the last right paw. Opposite paws receive saline injections for the control experiment. Edema reactions are evaluated 3 hours later.

The second test

Hypersensitivity edema for delayed mouse paw type (DTH-M)

Groups of mice (n = 8-10) of CD-I males weighing between 25-30 g were sensitized 1 by subcutaneous injection of 1 mg methylated serum bovine albumin (MBSA) in volumes of 0.2 ml saline / emulsion adjuvant, Freund- a (FCA). Negative control groups receive FCA saline / emulsion injections. The DHT reactions of paw edema were evaluated 24 hours after challenge in the right hind paw berry with 0.1 mg MBSA in volumes of 0.05 ml saline on day 7 after sensitization. Opposite paws receive saline injections for the control experiment. The test compounds or vehicle for the control experiment are administered orally once daily on days 4, 5, and 6 and twice daily on day 7, 1 hour before and 6 hours after MBSA excitation.

The third test

Hypersensitivity edema for delayed rat paw type (DTH-R)

Groups of rats (n = 8-12, CFHB males weighing between 160-180 g) were sensitized by subcutaneous injection into the tail base with volumes of 0.1 ml FCA. Negative control groups receive injections of Freund's uncompetitive adjuvants. The reactions of DTK paw edema were evaluated 24 hours after challenge in the posterior right paw berry with 0.4 ml of Mycobacterium tuberculosis antigen extract in volumes of 0.2 ml saline on day 7 after sensitization. Opposite paws receive saline injections for the control experiment.

Test compounds are administered orally once daily on days 4, 5, and 6 and twice daily on day 7, 1 hour before and 6 hours after antigen challenge.

TABLE II

-33TABLE II (continued)

The results of these tests are given in Table II. Doses are given in units of mg / kg p.o.

For ROUSSEL UCLAF

35, Bd. Des Invalides 75007 Paris, France:

Claims (11)

PATENT APPLICATIONS ί. New 3-cycloalkyl 1-propanamides according to the general formula (I): in which: R | represents a cycloalkyl group comprising 3-6 carbon atoms, R2 represents a hydrogen atom, an alkyl radical comprising 1-3 carbon atoms, R ₃ , R 4, Rg, Rg and Ry, identical or different, represent a hydrogen atom, a halogen atom, an alkyl radical normal or branched, comprising 1-6 carbon atoms, an alkoxy radical normal or branched, comprising 1-6 carbon atoms, an alkylthio radical containing 1-6 carbon atoms, radical ^ ^C ^ 2 ^ m ^-Cf: 3 '~ ^{0_ CH} 2 m ^_c ^ 3''where m represents a number between 0 and 3, radical -CF2 ~ Hal, -0CF2-Hal » - (CF ₂ ) _n -C-Ha ¹ and '"° < ^c F ₂ ) _n -C - Halp -S (CF ₂ ) _n ~ C" Halali H a 1 2 H a 1 2 Ha 1 2 O (CF ₂ ) _n -CF-Hal ₃ -CF ₃ , where n represents numbers between 1 and 3, Ha 1 and Hal _{2 are} identical or different and Hal and Hal ₃ represent a halogen atom, or 36Rg ^'R 4' ^R 5 ^'R 6 ^R 7 ^ιη * id ^one THICAL or different, present mented group, nitro, azido, nitrile, or a -CO-R', wherein R 'represents a radical of hydroxy, alkyl or alkoxy, which comprises 1- The 3 carbon atoms or R ^ and Rg together form the group -OC ^ -O ^- »their tautomeric forms as well as their addition salts with mineral or organic bases. 2. New 3-cycloalkyl-1-propanamides, as defined by formula (I) of claim 1, characterized by tea, that in a given formula I, ^r 3 » ^r 4> ^r 5» ^r 6 ^{and r} 7 'are identical or different hydrogen atom, fluorine, chlorine, bromine or iodine atom, methyl, ethyl, terbutyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethyl, pentafluoroethoxy, bromodifluoromethoxy, acetyl, hydroxycarbonyl, nitroxycarbonyl, methoxycarbonyl, nitro Rg together form the group 0CH2O-, R2 represents a hydrogen atom or a methyl radical, R1 has the indicated meaning as well as their addition salts with mineral or organic bases. 3. New 3-cycloalkyl-propanamides corresponding to formula (I) according to claim 1 or 2, characterized in that, in a given formula (I), R4 represents a cyclic propyl group, R2 represents a hydrogen atom or a methyl radical, Rg , R4, Rg, Rg and Ry, identical or different, represent a hydrogen atom, a fluorine, chlorine or iodine atom, a methyl, trifluoromethyl or nitro radical, as well as their addition salts with mineral or organic bases. 4. Any of the products of formula (I), the names of which are as follows: - 1- (4-nitrophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile and 1, - 1- (4-cyanophenylcarbamoyl) -2-cyclopropyl-2-oxopropionitrile and 1, - 1- (4-chloro 3-methylphenylcarbamoyl) -2-cyclopropyl-2-oxopropyl tri, - 1- (3-methyl 4-trifluoromethylphenyl 1-carbamoyl) -2-cyclic footwear 1-oxopropyl triethyl, - 1- (4-cyano 3-methylphenylcarbamoyl) 2-cyclopropyl 2-oxopropionitrile as well as their mineral and organic base addition salts. 5. A process for the preparation of new 3-cycloalkyl-propanamides defined by formula (I) of claim 1, as well as their salts, characterized in that the product of formula (II) is reacted: in which ^R 3 » ^R 4» ^R 5 » ^R 6 and ^R 7 ^{2e have the} indicated meaning, with an acid of formula (III) or a functional derivative of this acid: HO - CN (III) to obtain the product of formula (IV): 38'5 (IV) R R in which f? 2 »R3, R4, R5» Rg and R? 2e of the meanings sequentially reacted with sodium hydride, If necessary, in the presence of a catalyst such as imidazole and subsequently with the product of formula (V): Hal-CO-Rj (V) in which Hal represents a halogen atom, and Rj has the 2e meaning to give the corresponding product of formula (I) which is isolated and, if desired, converted to a salt. Preparation process according to claim 5, characterized in that the reaction of the product of formula (II) with an acid of formula (III) or with a functional derivative of this kisiipa is carried out in the presence of diisopropylcarbodiimide or dicyclohexylcarbodiimide in an anhydrous organic solvent such as tetrahydrofuran or dichloromethane that a functional derivative of an acid of formula (III), for example cyanoacetyl chloride, may be obtained in situ by the action of cyanoacetic acid on phosphorus pentachloride, to react the product of formula (IV) with sodium hydride in an anhydrous organic solvent such as tetrahydrofur an. Medicaments characterized by the fact that they consist of novel 3-cycloalkyl-propanamides of the formula (I) of claim 1, as well as their addition salts with pharmaceutically acceptable mineral or organic bases. 8. Tea-labeled medicaments consisting of novel 3-cycloalkyl-propanamides as defined in one of claims 2 to 4, as well as their addition salts with pharmaceutically acceptable mineral or organic bases. Pharmaceutical preparations labeled with tea to contain as active ingredient at least one of the medicaments as defined in any of claims 7 or 8. 10. As an industrial new (IV): products, products of formulas e (IV) in which l? 2, Rg, R4, Rg, Rg and R? meaning as defined in claim 1. 11. Like industrially new products, products of formula (IV), in which Rg, Rg and R are represented? a hydrogen atom, R4 represents a methyl radical, R2 and Rg have the meaning indicated in claim 1, excluding the meaning of a hydrogen atom and a methyl radical. For ROUSSEL UCLAF 35, Bd. Des Invalides 75007 Paris, France O D '· T *' I C A ALEXANDER JANZZIC LJUBLJANA, Re9ij & va24 Tel .: 311-236 -40New 3-Cycloalkyl-propanamides, their tautomeric forms, their salts, their preparation, use as a product, and THE PREPARATIONS THAT CONTAIN ABSTRACT The invention relates to new ones 3-Cycloalkyl 1-propanamide of formula (I): where R | represents C ^ .gc i ki oal k i 1; R 2 is H or C 1-6 alkyl; R3, R4, Rg, Rg and Ry are the same or different and represent H, halogen, C 1-6 alkyl, C 1-8 gal coke i, C | _gal k i 11 i o, - ^(CH 2 ⁾ m ^CF 3 '~ ° < ^CH 2 ⁾ m ^CF 3' ~ ^s < ^CH 2 ⁵ m ^CF 3 '~ ^CF 2 ^_Ha1 ' ° CF ₂ -Hal, F? F Z / ' ^{_ (CF} 2 ⁾ n ^c Z ^Ha1 l''° ( ^CF 2 ⁾ n' ^(: “ ^Ha1 l '-S (CF ₂ ) _n -C —Hal _χ or Hal ₂ ^X ' ^Hal 2 ^ Hal? -O (CF ₂ ) _n -CF-Hal 3 -CF 3, 'nitro, azido, nitrile or -CO-R', where m is 0 to 3, n is 1 to 3, Hal, Hal-p is Ha _{1 2} and Halg are halogen atoms and R 'is OH, C 1-6 alkyl, C 1-4 alkoxy, or R 3 and R 4 together form -O-CH ₂ -O-. The invention also includes tautomeric forms of the compounds of formula (I) as well as their salts with bases. A process for the preparation of a compound of formula (I) consists of the reaction with an acid of formula (III): HO or with its functional derivative to obtain formulas (IV): O the product further reacted with NaH, optionally in the presence of a torus and then with a compound of formula Ha1-C0-R _x to give a compound of formula (I). katali frogs age 1i